A central component of host defence systems against invading bacterial and viral pathogens involves the successful recognition of the pathogen, or components thereof, by cellular receptors which induce a signalling cascade resulting in stimulation of the immune system. An essential aspect of this system is T-cell recognition of major histocompatibility complex-(MHC)-peptide complexes.
CD4+ T-cells are able to recognize pathogen-derived peptides when such peptides are displayed in the context of MHC class II molecules, which are composed of an α- and β-chain originally assembled in the endoplasmic reticulum. These α- and β-chains associate with the invariant chain (Ii) which protects the peptide binding groove and facilitates trafficking of MHC class II molecules to endosomal compartments. In the endosomal compartments, Ii is cleared, leaving a peptide (CLIP) in the binding groove. The chaperone molecule HLA-DM facilitates replacement of CLIP by antigenic peptides. Mature MHC class II molecules loaded with antigenic peptide then migrate to the cell surface where they can be presented to CD4+ T-cells.
This system of antigen processing and the presentation of mature MHC class II molecules occurs in dendritic cells (DC), which are the only APC that can stimulate naïve T cells and induce a primary immune response. Thus, DC play a pivotal role in antigen-presentation and the induction of adaptive immunity. The capacity of DC to induce an immune response is dependent on their maturation state. It is thought that immature DC expressing low levels of MHC and T cell co-stimulatory molecules such as CD40, CD80, CD83 and CD86 on the cell surface capture antigens in the periphery. They then migrate to secondary lymphoid tissues and undergo a maturation process. Upon maturation, MHC molecules are redistributed from intracellular compartments to the cell surface which results in an increased capacity to present antigens. Concomitantly, the surface expression of co-stimulatory molecules which promote T cell activation is up-regulated. The cytokine profile secreted by DC is also dependent on their maturation stage. Cytokines produced by mature DC include IL-12, IL-1α/β, IL-18, IFN-α/β, IL-6, TNF-α, IL-10, and TGF-β. The DC cytokine profile finally determines the Th1/Th2-outcome of the immune response. That is, antigens that induce IL-12 secretion by DC induce Th1 differentiation while antigens that do not induce IL-12 production promote Th2 differentiation.
Many of the regulatory processes involved in DC maturation remain unknown. In particular, many of the molecular signalling pathways that are involved when MHC class II molecules undergo changes in localization from endosomal structures in immature DC to the plasma membrane in mature DC remain unclear.
Chaperonin 10 (Cpn10) is a highly conserved mitochondrial chaperone playing an essential role in protein folding. Cpn10 has also been shown to be involved in a number of immunomodulatory activities, for example, inhibition of nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines, both in vitro and in vivo. The present invention is predicated on the surprising and unexpected finding that Cpn10 has the capacity to modulate APC function, including redistribution of MHC molecules from intracellular compartments to the cell surface in DC, and APC-mediated activation of T cells.